Short-Term Impact of Low-Intensity Exercise with Blood Flow Restriction on Mild Knee Osteoarthritis in Older Adults: A Pilot Study.

This pilot study aimed to investigate the immediate impact of low-intensity exercises with blood flow restriction (BFR) on older adults with knee osteoarthritis (KOA). Fifteen patients with KOA who were over 50 years old, participated and underwent low-intensity resistance knee exercises at 30% of their one-repetition maximum with BFR three times/week for two weeks. Pre- and post-exercise assessments included pain levels, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, isokinetic knee strength, lower extremity muscle volume (via leg circumference and muscle thickness), functional performance tests (timed up-and-go [TUG] and sit-to-stand [STS]), skeletal muscle index (SMI) using bioelectrical impedance analysis, and handgrip strength (HGS). Post-exercise, there was a significant reduction in pain. WOMAC scores showed significant improvements across all three domains: pain, stiffness, and physical function. In the TUG and STS tests, completion times were significantly reduced. Thigh and calf circumferences, as well as thigh muscle thickness significantly increased after exercise. Post-exercise SMI and HGS also significantly increased. However, isokinetic knee strength did not show significant changes. In conclusion, low-intensity BFR exercises provide immediate benefits in symptoms and physical performance for patients with KOA, potentially inducing local and systemic muscle mass increase, even after a short-term intervention.

Comparative efficacy of vericiguat to sacubitril/valsartan for patients with heart failure reduced ejection fraction: Systematic review and network meta-analysis.

BACKGROUND: Despite the established efficacy of vericiguat compared to placebo, uncertainties remain regarding its comparative efficacy to sacubitril/valsartan for patients with heart failure reduced ejection fraction (HFrEF). This study aimed to assess the relative efficacy of vericiguat and sacubitril/valsartan through a systematic review, network meta-analysis, and non-inferiority tests. METHODS: A systematic review was conducted to identify the randomized phase 3 clinical trials involving vericiguat and sacubitril/valsartan. The hazard ratios (HRs) with 95% confidence intervals (CI) for cardiovascular death (CVD) and hospitalization due to HF (hHF) were extracted from these trials and synthesized via network meta-analysis. Non-inferiority testing of vericiguat was performed using a fixed-margin method with a predefined non-inferiority margin (1.24). Sensitivity analyses explored the impact of the time from hHF to screening. RESULTS: Among the 1366 studies, two trials (VICTORIA and PARADIGM-HF) met the inclusion criteria. Network meta-analysis demonstrated that the HR for CVD or hHF with vericiguat did not significantly differ from that for sacubitril/valsartan (HR: 0.88, 95% CI:0.62-1.23). The upper limit of the 95% CI was less than the predefined margin of 1.24, confirming vericiguat's non-inferiority to sacubitril/valsartan. Sensitivity analyses affirmed the robustness of the base-case results. CONCLUSION: Vericiguat exhibited a comparable risk of CVD or hHF when contrasted with sacubitril/valsartan. Importantly, in patients with HFrEF, vericiguat's efficacy was not statistically inferior to that of sacubitril/valsartan. These findings reinforce the potential of vericiguat as a viable treatment option for this patient population.

Random intercept hierarchical linear model for multi-regional clinical trials.

In multi-regional clinical trials, hierarchical linear models have been actively studied because they can reflect that patients in the same region share common intrinsic and extrinsic factors. In this paper, we investigate the statistical properties of the hierarchical linear model including a random effect in the intercept. The big advantage of the random intercept hierarchical linear model is that it can control the type I error rates of testing the overall treatment effect when there are no or clinically negligible regional differences in the treatment effect. Moreover, we compare the pros and cons with the hierarchical linear model in which the random effect is included in the slope. For the two hierarchical linear models, the model selection criteria are determined according to the magnitude of the difference in treatment effect across the regions, and we provide the criteria through simulation studies.

Hand Grip Strength, Osteoporosis, and Quality of Life in Middle-Aged and Older Adults.

Background and Objectives: Hand grip strength (HGS) and osteoporosis are known to be closely related to the health condition of the elderly, respectively. Comprehensive studies including adults over middle age were insufficient. This study aimed to investigate the relationship between HGS with osteoporosis and health-related quality of life (HRQoL) in adults aged >40 years. Materials and Methods: This cross-sectional analysis included data from 13,966 people aged >40 years between 2015 to 2018 provided by the Korea National Health and Nutrition Examination Survey. The HGS was divided into strong and weak quartiles, defined as the highest and lowest quartiles, respectively. We used the European Quality of Life Scale-Five dimensions (EQ-5D) for HRQoL. We performed multiple logistic regression and post hoc analysis to confirm the relationship between the four groups and HRQoL. Results: Osteoporotic patients with weak HGS showed the lowest EQ-5D index (0.87 ± 0.01) among all groups and had a significantly impaired HRQoL in all EQ-5D dimensions, at least 1.75 times more than healthy individuals with strong HGS (0.95 ± 0.00). Osteoporotic patients with weak HGS showed, notably, 2.68 times more impaired mobility compared to healthy individuals with strong HGS among all five dimensions of the EQ-5D. In self-care, significant sex differences in impaired HRQoL were observed (males 6.03, 2.23-16.35; females 2.51, 1.70-3.71). Conclusions: Weak HGS and the presence of osteoporosis were associated with low HRQoL, respectively. Middle-aged and older adults with both weak HGS and osteoporosis showed poorer HRQoL compared to healthy middle-aged and older adults. This suggests that HGS is a possible factor for predicting poor HRQoL in adults aged >40 years with or without osteoporosis. It is necessary to assess the risk of low HRQoL by measuring HGS and confirming whether osteoporosis is accompanied in adults over middle age.

Development of a low-melting-point eutectic salt and evaluation of its discharge performance for light weight thermal batteries.

This paper proposes low-melting-point eutectic salts containing RbCl as electrolytes for light weight thermal batteries. The handleability of the eutectic salts was remarkably improved for commercialisation. Their performance as thermal battery molten-salt electrolytes was verified using tests on a single cell and a 12-cell stacked battery.

Impact of Hospital Volume of Percutaneous Coronary Intervention (PCI) on In-Hospital Outcomes in Patients with Acute Myocardial Infarction: Based on the 2014 Cohort of the Korean Percutaneous Coronary Intervention (K-PCI) Registry.

BACKGROUND AND OBJECTIVES: The relationship between the hospital percutaneous coronary intervention (PCI) volumes and the in-hospital clinical outcomes of patients with acute myocardial infarction (AMI) remains the subject of debate. This study aimed to determine whether the in-hospital clinical outcomes of patients with AMI in Korea are significantly associated with hospital PCI volumes. METHODS: We selected and analyzed 17,121 cases of AMI, that is, 8,839 cases of non-ST-segment elevation myocardial infarction and 8,282 cases of ST-segment elevation myocardial infarction, enrolled in the 2014 Korean percutaneous coronary intervention (K-PCI) registry. Patients were divided into 2 groups according to hospital annual PCI volume, that is, to a high-volume group (≥400/year) or a low-volume group (<400/year). Major adverse cardiovascular and cerebrovascular events (MACCEs) were defined as composites of death, cardiac death, non-fatal myocardial infarction (MI), stent thrombosis, stroke, and need for urgent PCI during index admission after PCI. RESULTS: Rates of MACCE and non-fatal MI were higher in the low-volume group than in the high-volume group (MACCE: 10.9% vs. 8.6%, p=0.001; non-fatal MI: 4.8% vs. 2.6%, p=0.001, respectively). Multivariate regression analysis showed PCI volume did not independently predict MACCE. CONCLUSIONS: Hospital PCI volume was not found to be an independent predictor of in-hospital clinical outcomes in patients with AMI included in the 2014 K-PCI registry.

Efficacy and Tolerability of Pitavastatin Versus Pitavastatin/Fenofibrate in High-risk Korean Patients with Mixed Dyslipidemia: A Multicenter, Randomized, Double-blinded, Parallel, Therapeutic Confirmatory Clinical Trial.

PURPOSE: Dyslipidemia is an important risk factor for cardiovascular disease (CVD). Statins are known to effectively reduce not only low-density lipoprotein cholesterol (LDL-C) level but also death and nonfatal myocardial infarction due to coronary heart disease. The risk for CVD from atherogenic dyslipidemia persists when elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C) levels are not controlled with statin therapy. Therefore, statin/fenofibrate combination therapy is more effective in reducing CVD risk. Here, we assessed the efficacy and tolerability of pitavastatin/fenofibrate combination therapy in patients with mixed dyslipidemia and a high risk for CVD. METHODS: This multicenter, randomized, double-blind, parallel-group, therapeutic-confirmatory clinical trial evaluated the efficacy and tolerability of fixed-dose combination therapy with pitavastatin/fenofibrate 2/160 mg in Korean patients with a high risk for CVD and a controlled LDL-C level (<100 mg/dL) and a TG level of 150-500 mg/dL after a run-in period with pitavastatin 2 mg alone. In the 8-week main study, 347 eligible patients were randomly assigned to receive pitavastatin 2 mg with or without fenofibrate 160 mg after a run-in period. In the extension study, patients with controlled LDL-C and non-HDL-C (<130 mg/dL) levels were included after the completion of the main study. All participants in the extension study received the pitavastatin/fenofibrate combination therapy for 16 weeks for the assessment of the tolerability of long-term treatment. FINDINGS: The difference in the mean percentage change in non-HDL-C from baseline to week 8 between the combination therapy and monotherapy groups was -12.45% (95% CI, -17.18 to -7.72), and the combination therapy was associated with a greater reduction in non-HDL-C. The changes in lipid profile, including apolipoproteins, fibrinogen, and high-sensitivity C-reactive protein from baseline to weeks 4 and 8 were statistically significant with combination therapy compared to monotherapy at all time points. Furthermore, the rates of achievement of non-HDL-C and apolipoprotein B targets at week 8 in the combination therapy and monotherapy groups were 88.30% versus 77.98% (P = 0.0110) and 78.94% versus 68.45% (P = 0.0021), respectively. The combination therapy was well tolerated, with a safety profile similar to that of statin monotherapy. IMPLICATIONS: In these Korean patients with mixed dyslipidemia and a high risk for CVD, combination therapy with pitavastatin/fenofibrate was associated with a greater reduction in non-HDL-C compared with that with pitavastatin monotherapy, and a significantly improvement in other lipid levels. Moreover, the combination therapy was well tolerated, with a safety profile similar to that of statin monotherapy. Therefore, pitavastatin/fenofibrate combination therapy could be effective and well tolerated in patients with mixed dyslipidemia. ClinicalTrials.gov identifier: NCT03618797.

Efficacy and Safety of Omega-3 Fatty Acids in Patients Treated with Statins for Residual Hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Cardiovascular risk remains increased despite optimal low density lipoprotein cholesterol (LDL-C) level induced by intensive statin therapy. Therefore, recent guidelines recommend non-high density lipoprotein cholesterol (non-HDL-C) as a secondary target for preventing cardiovascular events. The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (OM3-FAs) in combination with atorvastatin compared to atorvastatin alone in patients with mixed dyslipidemia. METHODS: This randomized, double-blind, placebo-controlled, parallel-group, and phase III multicenter study included adults with fasting triglyceride (TG) levels ≥200 and <500 mg/dL and LDL-C levels <110 mg/dL. Eligible subjects were randomized to ATOMEGA (OM3-FAs 4,000 mg plus atorvastatin calcium 20 mg) or atorvastatin 20 mg plus placebo groups. The primary efficacy endpoints were the percent changes in TG and non-HDL-C levels from baseline at the end of treatment. RESULTS: After 8 weeks of treatment, the percent changes from baseline in TG (-29.8% vs. 3.6%, P<0.001) and non-HDL-C (-10.1% vs. 4.9%, P<0.001) levels were significantly greater in the ATOMEGA group (n=97) than in the atorvastatin group (n=103). Moreover, the proportion of total subjects reaching TG target of <200 mg/dL in the ATOMEGA group was significantly higher than that in the atorvastatin group (62.9% vs. 22.3%, P<0.001). The incidence of adverse events did not differ between the two groups. CONCLUSION: The addition of OM3-FAs to atorvastatin improved TG and non-HDL-C levels to a significant extent compared to atorvastatin alone in subjects with residual hypertriglyceridemia.

Binder-Free Cathode for Thermal Batteries Fabricated Using FeS2 Treated Metal Foam.

In this study, we fabricated a cathode with lower amounts of additive materials and higher amounts of active materials than those of a conventional cathode. A thermal battery was fabricated using FeS2 treated foam as the cathode frame, and its feasibility was verified. X-ray diffraction, transmission electron microscopy, and scanning electron microscopy were used to analyze the effects of thermal sulfidation temperature (400 and 500°C) on the structure and surface morphology of the FeS2 foam. The optimal temperature for the fabrication of the FeSx treated foam was determined to be 500°C. The FeS2 treated foam reduced the interfacial resistance and improved the mechanical strength of the cathode. The discharge capacity of the thermal battery using the FeS2 treated foam was about 1.3 times higher than that of a thermal battery using pure Fe metal foam.

Sample Size Calculations for Combination Drugs of 2 Monotherapies With a Single Approved Dose Level: Binary Endpoint Cases.

BACKGROUND: In this article, we study the sample size calculations for the combination drugs of 2 monotherapies with a single approved dose level when the primary endpoints are binary. METHODS: Two study cases are examined: In the first, each monotherapy has the same indication, while in the second, each monotherapy has a different indication. The sample sizes are calculated by using an asymptotic joint distribution of test statistics and employing unequal allocation for 3 popular measures of 2 proportions: the risk difference, the log relative risk, and the log odds ratio. RESULTS: Results show that our proposed method produces smaller total sample sizes compared with the heuristic method. CONCLUSIONS: The total sample sizes can be reduced by incorporating unequal allocation and dependency between 2 test statistics.

Bioequivalence data analysis for the case of separate hospitalization.

A bioequivalence study is usually conducted with the same-day drug administration. However, hospitalization is occasionally separated for logistical, operational, or other reasons. Recently, there was a case of separate hospitalization because of difficulties in subject recruitment. This article suggests a better way of bioequivalence data analysis for the case of separate hospitalization. The key features are (1) considering the hospitalization date as a random effect than a fixed effect and 2) using "PROC MIXED" instead of "PROC GLM" to include incomplete subject data.

Drip, Ship, and On-Demand Endovascular Therapy for Acute Ischemic Stroke.

BACKGROUND: The "drip and ship" approach can facilitate an early initiation of intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) at community hospitals. New endovascular treatment modalities, such as stent retrieval, have further improved the rate of safe and successful recanalization. We assessed the clinical outcomes of on-demand endovascular therapy in patients with AIS who were transported to a comprehensive stroke center under the "drip and ship" paradigm. METHODS: This retrospective study evaluated prospectively registered patients with acute large vessel occlusions in the anterior circulation who underwent endovascular recanalization after IVT at our regional comprehensive stroke center between January 2011 and April 2014. Clinical outcomes and neuroradiological findings were compared between patients who received IVT at the center (direct visit, DV) and at a community hospital (drip and ship, DS). RESULTS: Baseline characteristics such as age, initial National Institutes of Health Stroke Scale (NIHSS) score, and risk factors for stroke were similar, and most patients underwent endovascular therapy with a Solitaire stent (81.9% vs. 89.3% for DV and DS, respectively, P = 0.55). The average initial NIHSS score was 12.15 ± 4.1 (12.06 vs. 12.39 for DV and DS, respectively, P = 0.719). The proportions of long-term favorable outcomes (modified Rankin Scale score ≤ 2 at 90 days) and successful recanalization (Thrombolysis in Cerebral Ischemia score ≥ 2b) were not significantly different (P = 0.828 and 0.158, respectively). The mortality rates and occurrences of symptomatic intracerebral hemorrhage were not significantly different (P = 0.999 and 0.267, respectively). CONCLUSIONS: The "drip and ship" approach with subsequent endovascular therapy is a feasible treatment concept for patients with acute large vessel occlusion in the anterior circulation that could help improve clinical outcomes in patients with AIS.

Creutzfeldt-Jakob Disease Presenting With Dizziness and Gaze-Evoked Nystagmus: A Case Report.

Sporadic Creutzfeldt-Jakob disease (CJD) is clinically characterized by rapidly progressive dementia combined with other cardinal symptoms, such as myoclonus, visual or cerebellar disturbances, extrapyramidal or pyramidal disturbance, and akinetic mutism. However, as an initial manifestation, focal neurologic deficits other than the aforementioned or nonspecific generalized symptoms may lead to a misdiagnosis or a delayed diagnosis. The authors report a case of 66-year-old male patient with sporadic CJD who had dizziness, gaze-evoked nystagmus (GEN), and other central eye signs (impaired smooth pursuit, saccadic dysmetria) as an initial manifestation without dementia. The central eye signs led us to perform brain magnetic resonance images, which showed abnormal cortical high-signal intensity in both the cerebral and cerebellar hemispheres including the vestibulocerebellum. We reached a presumptive diagnosis of CJD, but the findings did not meet diagnostic criteria for probable CJD at that time. Three weeks after the initial work-ups, the patient presented with typical neurological findings of CJD: rapidly progressive dementia, akinetic mutism, and myoclonus of the left arm. Cerebrospinal fluid was positive for 14-3-3 protein, and electroencephalography showed periodic sharp wave complexes. In this patient, GEN and other central eye signs provided diagnostic clues for CJD. These unusual neurological manifestations may help physicians have a thorough knowledge of early deficits of CJD.

Avoiding ambiguity with the Type I error rate in noninferiority trials.

This review article sets out to examine the Type I error rates used in noninferiority trials. Most papers regarding noninferiority trials only state Type I error rate without mentioning clearly which Type I error rate is evaluated. Therefore, the Type I error rate in one paper is often different from the Type I error rate in another paper, which can confuse readers and makes it difficult to understand papers. Which Type I error rate should be evaluated is related directly to which paradigm is employed in the analysis of noninferiority trial, and to how the historical data are treated. This article reviews the characteristics of the within-trial Type I error rate and the unconditional across-trial Type I error rate which have frequently been examined in noninferiority trials. The conditional across-trial Type I error rate is also briefly discussed. In noninferiority trials comparing a new treatment with an active control without a placebo arm, it is argued that the within-trial Type I error rate should be controlled in order to obtain approval of the new treatment from the regulatory agencies. I hope that this article can help readers understand the difference between two paradigms employed in noninferiority trials.

Statistical assessment of biosimilarity based on the relative distance between follow-on biologics for binary endpoints.

A new three-arm parallel design was recently proposed to investigate the biosimilarity between a biological product and a reference product by using the relative distance. The purpose of this article is to extend their results to binary endpoints for three popular metrics: the risk difference, the log relative risk, and the log odds ratio. The relative distances based on the three metrics are defined, and corresponding test procedures are developed. The type I error rates and powers are investigated theoretically and empirically.

Characterization of the crawling activity of Caenorhabditis elegans using a Hidden Markov model.

The locomotion behavior of Caenorhabditis elegans has been studied extensively to understand the respective roles of neural control and biomechanics as well as the interaction between them. Constructing a mathematical model is helpful to understand the locomotion behavior in various surrounding conditions that are difficult to realize in experiments. In this study, we built three hidden Markov models (HMMs) for the crawling behavior of C. elegans in a controlled environment with no chemical treatment and in a formaldehyde-treated environment (0.1 and 0.5 ppm). The organism's crawling activity was recorded using a digital camcorder for 20 min at a rate of 24 frames per second. All shape patterns were quantified by branch length similarity (BLS) entropy and classified into four groups using the self-organizing map (SOM). Comparison of the simulated behavior generated by HMMs and the actual crawling behavior demonstrated that the HMM coupled with the SOM was successful in characterizing the crawling behavior. In addition, we briefly discussed the possibility of using the HMM together with BLS entropy to develop bio-monitoring systems to determine water quality.

Using hidden Markov models to characterize termite traveling behavior in tunnels with different curvatures.

Subterranean termites live underground and build tunnel networks to obtain food and nesting space. After obtaining food, termites return to their nests to transfer it. The efficiency of termite movement through the tunnels is directly connected to their survival. Tunnels should therefore be optimized to ensure highly efficient returns. An optimization factor that strongly affects movement efficiency is tunnel curvature. In the present study, we investigated traveling behavior in tunnels with different curvatures. We then characterized traveling behavior at the level of the individual using hidden Markov models (HMMs) constructed from the experimental data. To observe traveling behavior, we designed 5-cm long artificial tunnels that had different curvatures. The tunnels had widths (W) of 2, 3, or 4mm, and the linear distances between the two ends of the tunnels were (D) 20, 30, 40, or 50mm. High values of D indicate low curvature. We systematically observed the traveling behavior of Coptotermes formosanus shiraki and Reticulitermes speratus kyushuensis and measured the time (τ) required for a termite to pass through the tunnel. Using HMM models, we calculated τ for different tunnels and compared the results with the τ of real termites. We characterized the traveling behavior in terms of transition probability matrices (TPM) and emission probability matrices (EPM) of HMMs. We briefly discussed the construction of a sinusoidal-like tunnels in relation to the energy required for termites to pass through tunnels and provided suggestions for the development of more sophisticated HMMs to better understand termite foraging behavior.

Combination of honokiol and magnolol inhibits hepatic steatosis through AMPK-SREBP-1 c pathway.

Honokiol and magnolol, as pharmacological biphenolic compounds of Magnolia officinalis, have been reported to have antioxidant and anti-inflammatory properties. Sterol regulatory element binding protein-1 c (SREBP-1 c) plays an important role in the development and processing of steatosis in the liver. In the present study, we investigated the effects of a combination of honokiol and magnolol on SREBP-1 c-dependent lipogenesis in hepatocytes as well as in mice with fatty liver due to consumption of high-fat diet (HFD). Liver X receptor α (LXRα) agonists induced activation of SREBP-1 c and expression of lipogenic genes, which were blocked by co-treatment of honokiol and magnolol (HM). Moreover, a combination of HM potently increased mRNA of fatty acid oxidation genes. HM induced AMP-activated protein kinase (AMPK), an inhibitory kinase of the LXRα-SREBP-1 c pathway. The role of AMPK activation induced by HM was confirmed using an inhibitor of AMPK, Compound C, which reversed the ability of HM to both inhibit SREBP-1 c induction as well as induce genes for fatty acid oxidation. In mice, HM administration for four weeks ameliorated HFD-induced hepatic steatosis and liver dysfunction, as indicated by plasma parameters and Oil Red O staining. Taken together, our results demonstrated that a combination of HM has beneficial effects on inhibition of fatty liver and SREBP-1 c-mediated hepatic lipogenesis, and these events may be mediated by AMPK activation.

An improved preprocessing algorithm for haplotype inference by pure parsimony.

The identification of haplotypes, which encode SNPs in a single chromosome, makes it possible to perform a haplotype-based association test with disease. Given a set of genotypes from a population, the process of recovering the haplotypes, which explain the genotypes, is called haplotype inference (HI). We propose an improved preprocessing method for solving the haplotype inference by pure parsimony (HIPP), which excludes a large amount of redundant haplotypes by detecting some groups of haplotypes that are dispensable for optimal solutions. The method uses only inclusion relations between groups of haplotypes but dramatically reduces the number of candidate haplotypes; therefore, it causes the computational time and memory reduction of real HIPP solvers. The proposed method can be easily coupled with a wide range of optimization methods which consider a set of candidate haplotypes explicitly. For the simulated and well-known benchmark datasets, the experimental results show that our method coupled with a classical exact HIPP solver run much faster than the state-of-the-art solver and can solve a large number of instances that were so far unaffordable in a reasonable time.

Sample size calculations for the development of biosimilar products.

The most widely used design for a Phase III comparative study for demonstrating the biosimilarity between a biosimilar product and a renovator biological product is the equivalence trial, whose aim is to show that the difference between two population means of a primary endpoint is less than a prespecified equivalence margin. A well-known sample size formula for the equivalence trial is given by [Formula: see text] Since this formula is obtained based on the approximate power rather than the exact power, we investigate in this article the accuracy of the sample size formula. We conclude that the sample size formula is very conservative. Specifically, we show that the exact power based on the sample size calculated from the formula to have power [Formula: see text] is actually [Formula: see text] under some conditions. Therefore, the use of the sample size formula may cause a huge extra cost to biotechnology companies. We propose that the sample size should be calculated based on the exact power precisely and numerically. The R code to calculate the sample size numerically is provided in this article.